Anaphylaxis is a severe, rapid onset allergic reaction to insect stings or bites, foods, drugs, allergens, and can be idiopathic or exercise-induced. About 3 million American children suffer from food allergies (from peanuts, tree nuts, milk, eggs, fish, seafood and gluten) and according to a study released in 2008 by Centers for Disease Control and Prevention, there has been about an 18% increase in food allergy since 1997. Anaphylaxis occurs in about 1-16% of the US population and carries a 1% mortality rate. Epinephrine (adrenaline) is the uncontested cornerstone for the treatment of anaphylaxis, and can be life saving (Joint Task Force on Practice Parameters, 2005, J Allergy Clin Immunol 115: S483-S523; Lieberman P. 2003, Curr Opin Allergy Clin Immunol 3: 313-318; Simons F. E. R. 2004, J Allergy Clin Immunol 113: 837-844). Any delay in administration of epinephrine may be fatal. In 2003, 1.4 million intramuscular (IM) doses (EpiPen™) were prescribed in the United States and it increased to 1.9 million by 2007. About 100-200 people die annually in the US from food allergies.
Epinephrine, being the first-line of therapy for anaphylaxis, is available only as an injectable dosage form in ampoules or in autoinjectors (e.g., EpiPen™ and Adrenaclick™ Autoinjector). It is well absorbed systemically when administered by intramuscular (IM) or subcutaneous (SQ) routes. Subcutaneous injection has been shown to result in delayed (slower Tmax) and variable adrenaline absorption and hence not very effective (Simons F. E. R. et al. 1998, J Allergy Clin Immunol 101:33-37). IM injection, on the other hand, is favored over SQ route because of its rapid onset of action (Tmax) of about 3-8 minutes, and the duration of action between 1 and 4 hours. Based on historical and anecdotal evidence, a 0.3 mg dose of epinephrine, by subcutaneous (SQ) or intramuscular (IM) injection into the deltoid muscle, has been agreed upon as the dose required for the emergency treatment of adult anaphylaxis. Recent studies have also demonstrated that if 0.3 mg dose is administered IM into the laterus vascularis (thigh) muscle, epinephrine plasma concentrations are higher and occur more quickly than SQ or IM administration into the deltoid muscle (Joint Task Force on Practice Parameters, 2005, J Allergy Clin Immunol 115: S483-S523; Lieberman P. 2003, Curr Opin Allergy Clin Immunol 3: 313-318; Simons F. E. R. 2004, J Allergy Clin Immunol 113: 837-844)).
Thus, epinephrine injections are administered either manually or by automatic injectors preferably by IM route. However, there are many difficulties associated with manual SQ or IM administration of epinephrine, as discussed by Frew A. J. 2011, Allergy 66:15-24, that include: (i) well-known patient apprehension related to needle delivery, (ii) incorrect self-administration, (iii) extra-operational step of detaching the needle shield before removal of safety cap in syringe based injectors, (iv) possible loss of medication before reaching the target muscle, (v) requiring a trained or medical professional to administer the dose, and (vi) needle-stick injury. In addition, patients also find that the device is awkward to carry, especially as a second device is indicated in case of rebound anaphylaxis (20% of cases). Patients are therefore recommended to have at least one autoinjector at home, in the car, and at school or work, but few have them in all locations. As a result of these difficulties, the majority of at-risk diagnosed patients either does not fill their prescription for an autoinjector, or are unwilling to use it, instead going to the Emergency Department.
In addition, the currently marketed Epipen™ comes in two fixed doses of 0.15 mg for pediatric patients and 0.3 mg for adults, which often forces physicians to decide whether to under- or overdose a patient based on weight, especially in children. Hence, there exists a need in the market for more convenient, easy delivery of correct dosage form that does not require prior training in the use of the device, and increase compliance in persons prone to anaphylaxis. The intranasal formulations of present invention can be delivered using a small needle-free nasal spray device, which is simple to operate, easy to (self) administer and require no prior training to deliver therapeutic dose(s) thus enhancing compliance in individuals. Because the device is small, it is also easy to carry them unobtrusively in the pocket. Importantly, by providing 2 nasal sprays of the present formulation; a higher dose for adults, a lower dose for pediatric patients and an option to deliver the required dose (based on body weight by repeating the sprays) or a second dose in situations of rebound anaphylaxis, the present invention solves some of the important practical limitations of the autoinjector.
Delivery of epinephrine by oral route is also not recommended because of negligible bioavailability owing to its rapid and extensive metabolism in the gut and liver. Hence as an alternative approach, Rawas-Qalaji M. M. et al. (2013, J Allergy Clin Immunol. 131(1): 236-38; 2006, J Allergy Clin Immunol. 117(2): 398-403 and in WO2011109340) attempted to deliver epinephrine via the sublingual (SL) route. The authors used a very large loading dose of SL epinephrine (40 mg) probably due to its mucosal enzymatic degradation by COMT, as well as poor intrinsic mucosal transportation due to the strong vasoconstriction caused by epinephrine itself. The study further revealed that SL doses ranging from 5 to 40 mg epinephrine, as the bitartrate salt, could achieve plasma concentrations equivalent to IM injection. Despite the promise of this needle-free delivery approach, the disadvantage of vomiting associated with anaphylaxis and the panic in anaphylacting patients is a serious constraint to its practical use, making it highly unlikely that the SL tablet will stay in place under the tongue for sufficient time to be therapeutically effective. The intranasal spray formulations of the present invention, on the other hand, allows for a pharmaceutical dose to be delivered easily by the caretaker or patient as required and without major difficulties or undesired effects.
Early methods of nasal drug delivery employed relatively harsh methods to transport drugs across the nasal mucosa, including the use of damaging permeation enhancers such as bile salts. Consequently, many of the nasally delivered drugs were traditionally limited to nasal conditions such as rhinitis and nasal allergies, where the drugs act topically on the nasal mucosa rather than enter the systemic circulation. More recently, however, systemically acting nasally administered drugs, have been successfully developed.
The potential for delivering aqueous epinephrine solution via nasal mucosa route using a needleless high-pressure injection device was attempted by Yamada T. 2004, Anesth Prog 51: 56-61 in dogs. Using this delivery approach, the author reported achieving a peak (Tmax) epinephrine levels of ˜20 ng/mL in the blood at 15 seconds. The peak systolic pressure was 200% of baseline at 60 seconds and maintained for about 180 seconds, confirming physiological effects of epinephrine. Yet, this type of delivery is painful resulting in poor compliance and limited routine clinical utility. On the contrary, the intranasal formulation of the present invention is painless as it is delivered as a nasal spray, further contributing to enhanced patient compliance.
Pulmonary delivery of systemic epinephrine has been explored by Heilborn H. et al. 1986, J Allergy Clin Immunol. 78(6): 1174-79. The study compared the effects of high-dose pulmonary inhalation of epinephrine (i.e., 1.5 to 4.5 mg and 10 to 30 inhalations over several minutes from a metered-dose aerosol) versus subcutaneous injection in human subjects. The results showed that inhalation of 2 to 3 mg of epinephrine produces a gradual increase of epinephrine concentrations in plasma and hence may be beneficial to counteract the effects of bronchoconstriction in night-time asthma. Bronchomist™ was approved for this indication as an inhaled epinephrine mist. However, similar studies by Simons F. E. R. et al. 2000, Pediatrics 106(5): 1040-44 tested whether this could be used for anaphylaxis patients, and concluded that the number of inhalations required especially for children, the length of time to reach a threshold Tmax, and the unpleasant taste, made the pulmonary inhalation delivery route unacceptable for treating anaphylaxis. By providing an intranasal formulation that contains taste-masking agents and an optimal dose of epinephrine required to reach a Tmax equivalent to IM administered epinephrine, the present invention has overcome the limitations noted by the above-mentioned art.
The important intranasal epinephrine studies were conducted by Bleske B. E. et al. 1996 Am J Emerg Med 14: 133-38, who showed the systemic administration of epinephrine by the nasal route, for treatment of dogs during cardiopulmonary resuscitation (CPR). Although these authors observed a dose response, the absolute bioavailability appeared to be quite low, despite the use of 1% taurodeoxycholic acid solution (bile salts), which is now known to be a damaging mucosal permeation enhancer. Moreover, to minimize the severe local vasoconstriction caused by epinephrine that could potentially limit the mucosal absorption of epinephrine, they used pretreatment with intranasal phentolamine. The phentolamine pretreatment was administered 1 min prior to intranasal epinephrine dosing to enhance epinephrine absorption. To prevent its local degradation on the external nasal mucosa, the investigators used large loading doses of phentolamine ranging from 0.25 to 2.5 mg/kg/nostril, which amounts to 15 mg for a dog weighing 21 kg. The loading doses of epinephrine studied were 0.075, 0.75 and 7.5 mg/kg/nostril, which amounts to 157 mg/nostril for a dog weighing 21 kg. The greatest cardiac effects and the greatest epinephrine plasma concentrations of about ˜1,400 ng/mL were observed at 0.25 mg/kg/nostril of phentolamine and 7.5 mg/kg/nostril of epinephrine. For optimal treatment the authors used 7.5 mg/kg/nostril of epinephrine with 1% taurodeoxycholic acid as permeation enhancer after pretreatment with 0.75 mg/kg/nostril in about 1 ml each application. Although this study revealed the systemic delivery of epinephrine by the nasal route of administration, it had significant limitations for translation into clinical practice, including: (i) dosing that was not optimized, and it is also unclear whether phentolamine was used at its lowest level with no or minimal systemic exposure (which would have competed with epinephrine actions); (ii) the staged pre-dosing of phentolamine followed by epinephrine, which is totally impractical for real-world emergency treatment; (iii) the use of a very large loading dose of epinephrine (157 mg/nostril for a dog weighing 21 kg) and vasodilator (15 mg/nostril for a dog weighing 21 kg) (iv) use of large volumes such as 1.0 mL of solution per nostril and even at that volume, the epinephrine was noticed to crystallize out; this large volume in each nostril is also impractical for modern nasal aqueous sprays which use only 100-250 μl volume, and even at this lower volume quite a significant percentage of the aqueous dose slides off the more dense nasal mucosa and is swallowed; (v) the use of bile salts as mucosal permeation enhancers caused severe nasal mucosal tissue damage, and raises the question to what extent was the systemic delivery achieved due to the destruction of this tissue barrier, rather than by the actual penetration by epinephrine. This safety aspect of the study was a fatal flaw for clinical translation of this technology. This technology has lain dormant with no follow-up studies of any kind since 1996.
A nasal spray with a high loading dose of epinephrine (5 mg) was given to normal human subjects and was compared with intramuscular epinephrine in a recent study by Nakponetong K. et al. 2010, J Allergy Clin Immunol 125(2): Abstract 859. The study revealed a peak plasma concentration (Tmax) reached in 70±17 minutes. A Tmax of 70±17 minutes even at the higher loading dose of epinephrine, is insufficient to be of any utility in anaphylactic shock. Paradoxically, the data on the PK of the IM epinephrine injection with a Tmax of 69±19 minutes is also unacceptable.
Epinephrine formulations delivered by dry powder inhaler, which targets nasal mucosa of a subject and administered by breath-activated devices are described in two U.S. Pat. Nos. 7,954,491 and 7,947,742. However, such delivery of epinephrine may not be practically feasible in persons already in anaphylactic shock. Patient-activated devices are simply not suitable for treating children in an emergency anaphylactic setting. No successful systemic delivery or formulations were described.
Hence, despite the theoretical promise for the intranasal route for delivering epinephrine, there is a need for novel approaches for improving the intranasal (IN) epinephrine formulation for the treatment of anaphylaxis. As noted above, the investigation by Bleske B. E. et al. 1996 also had a number of significant practical limitations that prevented their clinical translation. And the lack of any successful follow-on studies has left this advance of 1996 frozen in time.
The present invention, however, has solved all the critical limitations of the above-mentioned art, especially the Bleske study. The first innovation is formulation. The formulation of the present invention permits lowering the epinephrine loading dose by the optional addition of a reversible topically-acting COMT inhibitor (to prevent epinephrine enzymatic degradation at the nasal mucosa), which may be co-administered with a low dose of a topically-acting vasodilator (phentolamine, to stop inhibition of mucosal transport by gross vasodilation) with epinephrine at the same time in the same dose. Added to these are one or more or combination of mucosal transit slowing agents, and modern permeation enhancers that are non-toxic to nasal tissues. The second innovation is to deliver this as a powder formulation, which itself is muco-adhesive and aids in mucosal dissolution and absorption. The resulting nasal route of administration to achieve systemic epinephrine in therapeutic doses sufficient to treat anaphylaxis, bronchospasm and coronary arrest is: (i) painless (no needle-phobia); (ii) easy to (self) administer or to have a caregiver administer; (iii) uses practical small doses of intranasal epinephrine formulation containing epinephrine, a vasodilator, COMT inhibitor, mucosal transit slowing agents, and modern permeation enhancers that are not toxic to nasal tissues.
The present invention represents the first major step forward in nasal epinephrine delivery since Bleske in 1996 and is neither anticipated nor is obvious to those with ordinary skills in the art.